Pharmacological characterization of the new histamine H4 receptor agonist VUF 8430

We compare the pharmacological profiles of a new histamine H-4 receptor agonist 2-(2-guanidinoethyl)isothiourea (VUF 8430) with that of a previously described H-4 receptor agonist, 4-methylhistamine. Radioligand binding and functional assays were performed using histamine H-4 receptors expressed in mammalian cell lines. Compounds were also evaluated ex vivo in monocyte-derived dendritic cells endogenously expressing H-4 receptors and in vivo in anaesthetized rats for gastric acid secretion activity. Both VUF 8430 and 4-methylhistamine were full agonists at human H-4 receptors with lower affinity at rat and mouse H-4 receptors. Both compounds induced chemotaxis of monocyte-derived dendritic cells. VUF 8430 also showed reasonable affinity and was a full agonist at the H-3 receptor. Agmatine is a metabolite of arginine, structurally related to VUF 8430, and was a H-4 receptor agonist with micromolar affinity. At histamine H-3 receptors, agmatine was a full agonist, whereas 4-methylhistamine was an agonist only at high concentrations. Both VUF 8430 and agmatine were inactive at H-1 and H-2 receptors, whereas 4-methylhistamine is as active as histamine at H-2 receptors. In vivo, VUF 8430 only caused a weak secretion of gastric acid mediated by H-2 receptors, whereas 4-methylhistamine, dimaprit, histamine and amthamine, at equimolar doses, induced 2.5- to 6-fold higher output than VUF 8430. Our results suggest complementary use of 4-methylhistamine and VUF 8430 as H-4 receptor agonists. Along with H-4 receptor antagonists, both agonists can serve as useful pharmacological tools in studies of histamine H-4 receptors.